While lifelong high-dose non specific immunosuppression currently successfully prevents the rejection of transplant allografts, these agents also render the recipient susceptible to a variety of infectious and neoplastic complications. "Tolerance" is the inactivation of the immune response to specific antigens while retaining normal responsiveness to unrelated antigens, and thus, is a major goal in prevention of allograft rejection. Factors influencing the direction of the immune response include route of antigen administration, and the oral and portal venous routes have been shown to distinctly promote tolerance induction. The 2C mouse is transgenic for the Class 1 MHC H-2Ld (Ld) alloantigen specific TCR. The allospecific CD8+ T cells are of high frequency in the 2C mouse which allows them to be identified, tracked. and enriched to a highly homogenous population with 1B2 mAb. Preliminary data presented here demonstrates that treatment with portal venous antigen can suppress the DTH response (a sign of global hyporesponsiveness). Using in vivo and in vitro techniques, the research proposed will rigorously test the mechanisms of oral and portal venous tolerance. These studies will determine the T cell subset which must be tolerized by oral or porta1 venous alloantigen to prevent allograft rejection, the cell type and alloantigen inducing the donor specific tolerance, and the effects oral or portal venous presensitization has on the anti-class l immune responses.